ABNORMAL RINGCLOSURE O F
Aug. 5 , 1958
talline precipitate appeared. The reaction mixture was cooled and filtered to give 7.3 g. (96%) of colorless needles, m.p. 270-272" dec. A sample of the product was recrystallized from water and dried in vacuo over PnOa a t 100" for 3 hours; m.p. 270-272" dec. Anal. Calcd. for C O H ~ F , O J / ~ HC, ~ O39.12; : H, 3.65; r'-,45.62. Found: C,39.19; H,3.61; N,45.59. 6-Aminomethylpurine (XIX).-A solution of 6-cyanopurine ( X V ) (0.29 g., 0.002 mole) in 15 ml. of absolute methanol was hydrogenated a t room temperature and atmospheric pressure in the presence of 0.2 g. of 570 palladiumcharcoal. The suspension was filtered, the precipitate washed with methanol and the combined filtrates evaporated in vacuo to yield 0.23 g. (757,) of needles, m.p. 181183" dec. The reaction product, which turned pink on exposure to air, was very soluble in water, ethanol, methanol and acetic acid and sparingly soluble in ether and benzene. A sample was purified by pouring a concentrated ethanol solution into ether. This treatment was repeated twice to yield a pale pink product, m.p. 183-185" dec. An ethanolic solution of this compound produced an intense crimson coloration on acidification. The picrate of XIX was prepared from aqueous solution in cold water. After four crystallizations from water, a light yellow product, m.p. 190" tlec. was obtained. [CONTRIBUTION FROM
THE
A
1,6-KETO ALDEHYDE
3937
Anal. Calcd. for C ~ H ~ N S . C ~ H ~C,N38.10; ~ O ~ : H, 2.66; N,29.62. Found: C, 37.94; H, 2.86; Tu', 29.47. Spectrophotometric and Dissociation Studies.-Spectrophotometric measurements were made with a Cary model 11 ultraviolet recording spectrophotometer (Applied Physics Corporation, Pasadena, Calif .) using matched I-cm. silica cells and techniques and buffers previously de~cribed.~? The apparent pK, values were determined using the methS , ~Parke ~ and Davis.40 ods described by Fox and S h ~ g a r , ~and
Acknowledgments.-The authors wish to thank Dr. George E . Brown, Dr. J. J. Fox, Dr. C. Chester Stock and Dr. D. A. Clarke for valuable advice and discussion. They wish to express their gratitude to Mr. Janis Vitols and Mr. Herbert s. Rosenkranz for assistance. (37) J. J. Fox, L. F. Cavalieri and N. Chang, THISJ O U R N A L , 76, 4315 (1953). (38) J. J. F o x and D. Shugar, B d 1 . soc. chim. Belg., 61, 44 (1952). (39) D. Shugar and J . J. Fox, Biochim. et Biophys. Acta, 9 , 199 (1953). (40) T. V. Parke and W. W. Davis, Anal. Chem , 26, 642 (1954).
NEWYORK21, N. Y .
hfERCK SHARP & DOHMERESEARCH LABORATORIES]
Studies in the Iridomyrmecin Series. Abnormal Ring Closure of a 1,6-Keto Aldehyde BY N. L. WENDLERAND H. L. SLATES RECEIVED MARCH6. 1958 An unusual ring closure of a 1,6-keto aldehyde derivative of a tetrahydrofuran is described.
The original work by Fusco, Trave and Vercellone' on the structure of iridomyrmecin and related terpenoid compounds isolated from various IrTridomyrmex species of ants led these authors to the proposal of a part structure for this substance. This part structure was based on the oxidation of iridomyrmecin to a nepetalinic acid whose structure had presumably been established by McElvain and Eisenbraun2 to be I (unknown configuration a t carbon designated by asterisk). Some time thereCHa H*,,C@,H
I
*-!,CO*H H
A
CHaH
Recently McElvain4 succeeded in converting nepetalic acid to isoiridomyrmecin in such a way as presumably to have established structure I1 for these substances. On the basis of structure I1 we undertook to synthesize iridomyrmecin as well as its epimer, and the present account reports our experience in this direction. Since the inception of our work, however, a further article by Cavil15 has appeared in which i t is now disclosed that through private communication with McElvain a change of group configurations in nepetalinic acid is necessary whereby formula IV now represents the structure of this key compound. Details concerning the chemistry necessitating revision of the previously CHa
I
after Cavill, Ford and Locksley3reported summary findings permitting the assignment of either structure I1 or I11 to iridomyrmecin and its epimer (epimeric a t the carbon designated by an asterisk). CH3
accepted structure I for nepetalinic acid which would have greatly enlightened this rather confused field were not revealed. We prepared the Diels-Alder adduct V6 from isoprene and maleic anhydride and reduced i t with lithium aluminum hydride to the diol VI. I1
I11
(1) R. Fusco, R . Trave and A. Vercellone, Chim. e Industr., 37, 958 (1955); 37, 251 (1955). (2) S. M. McElvain and E. J. Eisenbraun, THISJ O U R N A L , 77, 1599 (1955); 77, 3383 (1955). (3) G . W. K. Cavill. D. L. Ford and H. D Locksley, Chevziit?y & Industry, 465 (1956).
(4) S. M. McElvain and E. J. Eisenbraun, J . Org. Chem., 22, 976 (1957). (5) G. W. K. Cavill and H. D. Locksley, Australian J . Chem., 10, 352 (1957). (6) J. Baeseken and W. J. F. van der Gracht, Rec. tras. chim., 66, 1203 (1937); see also E . A. Farmer and F. L. Warren, J . Chem. Soc., 3221 (1931).
3035
Vol.
It had been observed previously7 that a 1,4-diol system is converted to the corresponding cyclic oxide by treatment of the mono- or dimesylate derivatives variously with basic reagents or lithium aluminum hydride, respectively. The latter of these techniques was unrewarding in the case of our diol ITI,whereas esterification with one equivalent of methanesulfonyl chloride in pyridine followed by treatment of the crude product with methanolic potassium hydroxide afforded 40-50y0 of the desired tetrahydrofuran derivative VII. On the other hand by employing Schotten-Bauniaiin conditions, whereby a stirred ether solution of VI containing p-toluenesulfonyl chloride n as treated dropwise with aqueous potassium hydroxide, yields of 7S-SO7, of the cyclic oxide V1I could be realized. Hydroxylation of VI1 with osmium tetroxide produced the crystalline diol VIII, m.p. 9.>-9s O .
C8H€.SO?Cl
I
J
OH -
so
CHzBr
A,,,\
l l ?
E CHaH
(9,800) instead of 237 mp expected for a ketone with structure A. The infrared spectrum exhibited a band at 3.67 p associated with the aldehydic function (C-HJ. Kuclear magnetic resonance measurements on this material also indicated unmistakably the C-II absorption a t 196 cycles on the low field side characteristic of the aldehyde group vith no evidence of an olefinic hydrogen; X formed a seniicarbazone, m.p. 21%2%0°, and a red 2,4-dinitrophenylhydrazone derivative, m.p. 214-21 1.3'. Finally oxidation of X n ith silver oxide proceeded smoothly v, ith formation of the carboxylic acid XI, imp. 100-1 02 ', conclusively establishing structure X for the cyclization products.
VI11
1.11
It had been anticipated that periodate cleavage of VI11 to the intermediate ketoaldehyde IX would, in keeping with precedent, ring close to the bicyclic Aa,a-ketone A. The latter might then have been successively hydrogenated to the cis-syn-cis-
x CHa
XI
CHI
The somewhat surprising consequence of cyclization of the 1,6-ketoaldehyde IX to give X is in some measure mitigated by the low yield in which i t was formed. Cyclizations were effected variously employing potassium hydroxide, potassium t-butoxide, piperidine acetate and basic alumina and all gave essentially the same result.
Experimental* H
IX
A
7
saturated ketone B and epiinerized to the cis-syntrans-ketone C. Honiologation of C would have led to the bicyclic acid D capable of conversion with hydrogen bromide to the bromolactone E. Reductive debromination of E should in turn have provided 11. Since the position alpha to the lactone carbonyl is epimerizable to what is most probably the equatorial configuration, the above sequence would have constituted a stereo-selective synthesis of isoiridoniyrmecin (and correspondingly iridomyrmecin) . In actuality, cleavage of the diol IT11 with sodium metaperiodate followed by cyclization under a variety of conditions consistently produced the Aa,P-imsanir,ted aldehyde X, instead of the ketone A, as t - h ~only volatile product that could be characterized. The crude aldehyde exhibited ultraviolet absorption v;ith 248 rnp
~z:i~~
( 7 ) G. Stork, L. J. Friedman, E E van Tamelen and .4.W. Burgstahler. THISJ O W R X A I . , 7 6 , 384 (1953).
l-Methyl-4,5-bis-hydroxymethylcyclohex-l-ene (VI).--X solution of 25 g. of adduct V (m.p. 63.5-64.5') in 300 cc. of ether was added to 25 g. of lithium aluminurn hydride in1 1. of ether a t room temperature at such a rate as to maintain reflux. .After the addition was complete the reaction mixture was refluxed for 2 hours, then chilled in ice and decomposed with i 5 cc. of ethyl acetate followed by 450 cc. of saturated sodium sulfate solution. The ether solution of V I was decanted from the salts, dried over magnesium sulfate and evaporated to a viscous oil, wt. 20 g. -Inanalytical sample was obtained by distillation at 140' and 0.7-0.8 mm. Anal. Calcd. for Cy€11602:C, 69.23; H,10.25. Found: C, 69.09; 13, 10.22. Formation of the Bicyclic Oxide VII. (A).-.4 solution of 25 g. of the diol VI in 100 cc. each of benzene and pyridine at 0' was treated dropwise with stirring with 18.4 g. ( 1 equiv.) of methanesulfonyl chloride in 50 cc. of benzene. The reaction mixture was allowed to stand overnight at 0-5' then diluted ivith water and the benzene layer separated and diluted with ether. The organic layer vias washed successivel!. with dilute hydrochloric acid and sodium bicarbonate, dried over magnesium sulfate and concentrated a t 30-40" t o an oil. The latter was dissolved in 100 cc. of methanol and treated with 20 g. of potassium hydroxide in 20 cc. of water _I_____
( 8 ) Melting points wprc taken o n a micro hot-stage apparutus arid are corrected.
THESYNTHESIS OF 1 , l '-BIAZIRIDINE
Aug. 5, 1958
3939
causing an immediate precipitation of sodium rnethanesulfonate. The reaction mixture was refluxed for 1 hour and then the methanol distilled in 2racuo to the point of turbidity. The reaction mixture a t this stage was diluted with saturated salt solution and extracted with petroleum ether which dissolved VI1 away from other insoluble organic impurities. The petroleum ether extract was dried and evaporated to a mobile oil with a terpene-like odor. Distillation of this oil afforded 11.1 g. of VII, b.p. 110' a t 45 mm. (54%). Anal. Calcd. for C0H140: C, 78.26; H, 10.15. Found: C, 78.28; H, 10.28. (B).-A solution of 10 g. of diol VI and 15 g. of p-toluenesulfonyl chloride in 50 cc. of ether was treated dropwise with stirring with a solution of 15 g. of potassium hydroxide in 50 cc. of water. After addition was complete the reaction mixture was heated for 1 hour on the steam-bath and worked up as in part A; yield 7 g. (SO'%) of VII. Preparation of Diol VI11 bv Osmium Tetroxide Hvdroxvlation of Oxide VI1.-A solutibn of 10 g. of oxide VIf in 25cc. of dioxane was treated with 25 g. of osmium tetroxide and allowed to stand a t room temperature for 2 days. At the end of this period the dark reaction mixture was decomposed by hydrogen s ~ l f i d e filtered ,~ through Celite and concentrated to a water-soluble oil, wt. 7.5 g. This oil crystallized on standing and could be recrystallized from ether, m.p. 95-98'. Anal. Calcd. for CgH1003: C, 62.81; H , 9.30. Found: C, 62.60; H , 9.38. Cleavage of VI11 to IX and Formation of the Bicyclic Ad-Aldehyde X. (A).-A solution of 575 mg. of crystalline diol VI11 in 2 cc. of tetrahydrofuran a t room temperature was treated with 750 mg. of sodium metaperiodate in 5 cc. of water. The reaction mixture was cooled slightly to offset the heat of reaction which was accompanied by the separation of sodium iodate. The reaction mixture was allowed to stand l hour, then concentrated in uacuo and the water-soluble keto aldehyde intermediate IX thoroughly extracted with ether. Evaporation of the ether left 360 mg. of a colorless oil which gave an immediate yellow precipitate with 2,4-dinitrophenylhydrazonereagent. This oil was dissolved in 15-20 cc. of benzene treated with 3 drops of pyridine and 2 drops of acetic acid and refluxed with a water separator for 1 hour. The reaction mixture was diluted with ether and washed successively with dilute hydrochloric acid,
--
potassium bicarbonate and saturated salt solution. The dried ether solution was concentrated and distilled a t 100" and 0.7 mm. to afford 100 mg. of crude aldehyde X with a 248 rnp, E 9800, Xmax 5.99 fi (conj C=O), 6.08 p (C=C), 3 . 6 7 (ald. ~ C-H); n.ni.r. 196 -. 2,4-Dinitrophenylhydrazone red crystals from ethyl aceAnal. Calcd. for CIState-methanol, m.p. 214-214.5'. Hla05N4:C, 54.22; H, 4.82; N, 16.87. Found: C, 54.48; H,5.02; N,16.70. Semicarbazone from methanol, m.p. 215-220'. Anal. Calcd. for C1oHloOnN3: C, 57.42; H, 7.18; N, 20.10. Found: C, 57.45; H , 7.01; N, 19.73. (B).-A solution of 1.72 g. of diol VI11 was cleaved in 20 cc. of water with 3 g. of sodium metaperiodate for 1 hour. The reaction solution was made alkaline with potassium hydroxide and warmed on the steam-bath to the amearance of turbidity. Extraction with ether afforded 150 mg. of 244 m p , E 9800. crude X, Ao:H (C).-A solution of 2 g. of diol VI11 was cleaved with 3 g. of sodium metaperiodate for 1hour and the product continuously extracted with ether. The ether solution was evaporated and the residue treated with 50 cc. of t-butyl alcohol containing 0.39 g. of potassium metal dissolved. The reaction mixture turned yellow and finally orange-red. After 15 minutes the reaction mas quenched with 10% hydrochloric acid, evaporated and worked up as described above. The product obtained in low yield exhibited 248 m p , E 7448. (D).-Results comparable to the foregoing mere experienced when the ether solution of the cleavage product IX was allowed to stand several hours on basic alumina and then eluted. Oxidation of the Bicyclic Aldehyde X to the Acid XI.A solution of 100 mg. of the aldehyde X in 2 cc. of ethanol was treated with silver oxide freshly prepared from 200 mg. of silver nitrate and 100 mg. of potassium hydroxide. The oxidation was allowed to proceed for 30 minutes with stirring and then filtered, evaporated and dissolved in ether. The acidic material was extracted with potassium bicarbonate. Acidification of t h e bicarbonate extract precipitated the acid XI in crystalline form. The latter was extracted with ether and crystallized from the same solvent, m.p. 100-102 O . Anal. Calcd. for CaH1203: C, 64.29; H , 7.14. Found: C, 61.09; II, 7.08.
(9) Method of D. H. R. Barton and D. Elad, J . Chem. S O ~ 2085 ., (1956).
RAHWAY, N. J.
[CONTRIBUTION FROM CHEMICAL DIVISION,AEROJET-GENERAL CORPORATIOX]
The Synthesis of 1 , l '-Biaziridine. A New Bicyclic System1 BY ALLENF. GRAEFEAND RALPHE. MEYER RECEIVED JASUARY 24, 1958 The preparation of I-haloaziridines from ethylenimine and hypohalite is described. The reaction of 1-chloroaziridine with 1-lithiumaziridine in ether was investigated, and evidence is presented that the isolated product is 1,l'-biaziridine. Some properties of this new bicyclic compound are presented.
Introduction During the course of a n investigation of the lower alkyl hydrazines in this Laboratory, i t became a matter of importance to synthesize the as yet unknown bicyclic compound, 1,1'-biaziridine (I). A method of preparation of the compound became available when i t was found that 1-chloroaziridine could be obtained from ethylenimine and aqueous hypochlorite. 1,l'-Biaziridine was then prepared from the reaction of 1-chloroaziridine with the known 1-1ithiumaziridine. (1) This investigation was carried out under a contract with the Office of Naval Research. (2) H . Gilman, et al., TEIIS JOURNAL, 67, 2106 (1945).
To our knowledge, no other hydrazine derivative has been prepared by this method. This may be the result of the ready dehydrohalogenation of alkylchloramines by alkylarnide anions since, in an attempt to prepare tetrametliylhydrazine from dimethylchloramine and dimethylamidomagnesium halide, Klages and co-workers reported amines as the only basic product^.^ I n the present synthesis (3) F. Klages, e l al., Ann., 847, 1 (1941).
